ABSTRACT This is a proposal to continue the Cystic Fibrosis (CF) Research and Translation Center at the University of California, San Francisco and collaborating institutions. The focus of our Center remains the discovery and advancement of novel small-molecule therapies for CF. The original proposal 15 years ago followed from 5 years of work establishing a unique academic drug discovery program in the laboratories of Dr. Verkman and collaborators to identify and characterize small-molecule modulators of CFTR. The proposed Center will fund four scientific Cores and an administrative Core to support the activities of 2 Pilot Projects and at least 22 CF- related projects. The Core directors are experienced CF investigators with recognized expertise in their areas of investigation and a history of productive collaboration. The Cores include: High-Throughput Screening (Core A, Alan Verkman, Director), Assays & Cell Models (Core B, Peter Haggie, Director), Chemistry (Core C, Mark Kurth (UC Davis) and Marc Anderson (San Francisco State University), co-Directors), and Animal Pharmacology & Models (Core D, Onur Cil, Director). Major focuses of projects utilizing the Cores include development of therapies for the `remaining 10%' of CF subjects that are not benefitted by available CFTR modulators, which include tailored modulators for rare and difficult-to-treat CFTR mutants, and mutation- agnostic therapies such as SLC26A4 (pendrin) inhibitors and SLC26A9 modulators; and therapies targeting gastrointestinal and renal complications of CF, such as SLC26A3 (DRA) inhibitors for CF constipation and enteric hyperoxaluria, and SLC26A6 (PAT-1) inhibitors for CF constipation and meconium ileus. The goal of the research to be enhanced by the Center remains the development of novel small-molecule therapies for CF that can be translated into the clinic.